title: Enantioselective Michael addition of 1,3-dicarbonyl compounds to a nitroalkene catalyzed by chiral squaramides - a key step in the synthesis of pregabalin.
abstract: Asymmetric organocatalytic 1,4-additions provide access to a large number of biologically relevant compounds. Chiral squaramides efficiently catalyse enantioselective Michael addition of 1,3-dicarbonyl compounds to aliphatic nitroalkenes. The resulting γ-nitro carboxylic derivatives were obtained in high yields and in high enantiomeric purities. Quantum chemical calculations helped us to devise a transition state model, which explains the observed stereochemical course of the addition. The best results were obtained with Meldrum's acid as a donor, with which enantiomeric purity of the Michael adduct was 97 : 3 e.r. Using this methodology pregabalin was synthesized in three steps in overall 52% yield.
authors.affiliation: Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynska dolina CH-2, SK-842 15 Bratislava, Slovakia. radovan.sebesta@fns.uniba.sk.
authors.forename: Rastislav
authors.initials: R
authors.lastname: Baran
authors.forename: Eva
authors.initials: E
authors.lastname: Veverková
authors.forename: Andrea
authors.initials: A
authors.lastname: Skvorcová
authors.forename: Radovan
authors.initials: R
authors.lastname: Sebesta
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D007659:Ketones / Q000737:chemistry*; D008958:Models, Molecular; D000069583:Pregabalin; D013237:Stereoisomerism; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000475:Alkenes; D000927:Anticonvulsants; D007659:Ketones; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid